It has been suggested that cell death not only plays an important role in basic control of the nervous system, the endocrine system and the immune system in higher organisms but also is deeply involved in many diseases (Thompson C. B., Science, Vol. 267, p. 1456-1462 (1995). Some diseases including, for example, autoimmune diseases such as systemic lupus erythematosus, neurodegenerative diseases due to cytotoxicity, organ transplantation injuries associated with organ transplantation etc. may be regarded as one due to influence of cell death where apoptosis is involved.
Factors causing cytotoxicity includes both an extraneous factor and an intrinsic factor. For an extraneous factor, those of which substantial existence as substance accelerating cytotoxicity have been established include TNF involved in the immune system (Zheng, L., et al., Nature, vol. 377, p. 348-351 (1995)), Fas ligand (Suda T., et al., Cell, vol. 75, p. 1169-1178 (1993)), glucocorticbids (Wyllie A. H., Nature, vol. 284, p. 555-556 (1980)), etc. An extraneous factor also includes lack of a growth factor indispensable to cell growth, such as erythropoietin, interleukins, nerve growth factor, or lack of nutritional factors. In these cases, cytotoxicity is induced by apoptosis caused by change in physiological conditions. Apoptosis may also be induced by non-physiological stresses such as radiation, temperature, anticancer agents, calcium ionophore, active oxygen, etc. In addition, necrosis may also be induced by burn, toxic substance, ischemia, attack by complements, infection with virulent virus, administration of overdose medicaments or overdose radiation.
For an intrinsic factor, there are changes in the metabolic system such as intracellular concentration of Ca2+, metabolism of nucleic acids, metabolism of amino acids, metabolism of energy, etc., which lead to cell death. Control of these apoptotic signals could have lead to protection from exacerbation of conditions of, prevention or treatment of, various diseases. However, at present, the mechanism is not so simple that mere control of the causal substance and factors that have hitherto been established cannot afford sufficient clinical application.
On the other hand, as substance that have hitherto been proved to inhibit cytotoxicity, intracellular factors such as bcl-2 and bcl-x are known that are believed to inhibit most of apoptotic signals (Boise L. H., et al., Cell, vol. 74, p. 597-608 (1993)). However, these agents must intracellularly be expressed for causing inhibition of cytotoxicity and effects can hardly be obtained by extracellular addition of these agents. Extracellular factors for inhibiting cytotoxicity have also been reported that inhibit apoptosis by active oxygen, including superoxide dismutase (hereinafter also referred to as “SOD”) (Greenlund L. J., et al., Neuron, vol. 14, p. 303-315 (1995)), catalase (Sandstrom P. A. and Buttke T. M., Proc. Natl. Acad. Sci. USA, vol. 90, p. 4708-4712 (1993)), and glutathione peroxidase (Kayanoki Y., et al., J. Biochem., vol. 119, p. 817-822 (1996)). However, cytotoxicity cannot effectively be inhibited by these extracellular factors alone.